Angiogenesis is an important cellular event in which vascular endothelial cells (ECs) proliferate, prune, and reorganize to form new vessels from preexisting vascular networks. There is compelling evidence that the development of a vascular supply is essential for normal and pathological proliferative processes. Delivery of oxygen and nutrients, as well as the removal of catabolic products, represent rate-limiting steps in the majority of growth processes occurring in multicellular organisms. Thus, it has been generally assumed that the vascular compartment is necessary not only for organ development and differentiation during embryogenesis, but also for wound healing and reproductive functions in the adult.
Angiogenesis is also implicated in the pathogenesis of a variety of disorders, including but not limited to, cancers, obesity, proliferative retinopathies, age-related macular degeneration, tumors, rosacea, atheroscleroses, rheumatoid arthritis (RA), cellular immunity, and psoriasis. Angiogenesis is a cascade of processes consisting of degradation of the extracellular matrix of a local venue after the release of proteases, proliferation of capillary ECs, and migration of capillary tubes toward the angiogenic stimulus. In view of the remarkable physiological and pathological importance of angiogenesis, much work has been dedicated to the elucidation of the factors capable of regulating this process.
Transmembrane-4 L six family member-1 (TM4SF1) was discovered in 1986 as “L6 antigen” or “tumor cell antigen” (Hellstrom et al. Cancer Res. 46: 3917-3923, 1986) because it was abundantly expressed on many cancer cells. Unexpectedly, it was also found to be weakly expressed on the vascular ECs of blood vessels supplying normal tissues (DeNardo et al. Int J Rad Appl Instrum B. 18: 621-631, 1991; Wright et al. Protein Sci. 9: 1594-1600, 2000; Richman et al. Cancer Res. 5916s-5920s, 1995; O'Donnell et al. Prostate. 37: 91-97, 1998). TM4SF1 is highly expressed by the EC lining the blood vessels supplying several human cancers (Shih et al. Cancer Res. 69: 3272-3277, 2009; Zukauskas et al. Angiogenesis. 14: 345-354, 2011), by the ECs of developing retinal vasculature (English et al. J Biomed Inform. 42: 287-295, 2009), and by the ECs of angiogenic blood vessels induced in mice with an adenovirus expressing VEGF-A (Shih et al. Cancer Res. 69: 3272-3277, 2009), though not by many other cell types (Shih et al. Cancer Res. 69: 3272-3277, 2009; Zukauskas et al. Angiogenesis. 14: 345-354, 2011).
Despite findings suggesting that TM4SF1 has potential as a vascular target for treating disorders associated with pathological angiogenesis, such as cancers, there remains an unmet need for compounds that target TM4SF1 (e.g., TM4SF1-specific binding polypeptides, e.g., anti-TM4SF1 antibodies, e.g., anti-human TM4SF1 antibodies) and are useful and scalable for commercial and therapeutic purposes.